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Background: Antidepressant effects have been demonstrated with both highfrequency left-sided repetitive transcranial magnetic stimulation (rTMS) (HFL-TMS) and low-frequency stimulation to the right prefrontal cortex (LFR-TMS). However, doubts remain about the extent of these reported treatment effects. Design and Methods: The study was a 6 week double-blind randomized sham-controlled trial of sequential bilateral rTMS (SBrTMS) in depression. The method consisted of 3 trains of LFR-TMS of 140 s duration at 1 Hz being applied daily followed immediately by 15 trains of 5 s duration of HFL-TMS at 10 Hz. Sham stimulation was applied using identical parameters, but with the coil angled at 45 degrees from the scalp resting on the side of one wing of the coil. Results: There was a significant difference in response between the two groups at the 2-week time-point (F(1,25) = 25.5, p < 0.001) and for the full duration of the study (F(5,44) = 3.9, p = 0.005). A significant proportion of the active study group met response (11/25) and remission criteria (9/25) by study end compared to the sham group (2 and 0/22). Interpretation: Bilateral rTMS treatment, involving the sequential application of both HFL-TMS and LFR-TMS, has substantial treatment efficacy in patients with treatment-resistant depression. The treatment response is clinically significant following 4–6 weeks of active treatment. Therefore this novel style of bilateral rTMS has the potential to become a substantive clinical intervention, although the study requires replication.